Method of preventing the reinfestation of dogs and cats by fleas

ABSTRACT

A method of treating fleas on dogs and cats by orally administering a larvicidally or ovicidally effective amount of flea growth inhibiting benzoylurea.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a continuation of Ser. No. 07/982,231, filed Nov. 25, 1992, nowabandoned, which in turn is a continuation of Ser. No. 07/502,805, filedApr. 2, 1990, now abandoned, which in turn is a continuation-in-part of(i) Ser. No. 06/893,763, filed Aug. 6, 1986, now abandoned, (ii) Ser.No. 07/310,257, filed Feb. 13, 1989, now U.S. Pat. No. 4,973,589, and(iii) Ser. No. 07/476,109, filed Jan. 30, 1990, now abandoned. Ser. No.07/310,257 is a continuation-in-part of Ser. No. 06/893,763 and Ser. No.07/476,109 is a continuation-in-part of Ser. No. 07/190,797, filed May6, 1988, now abandoned, which in turn is a continuation of Ser. No.07/038,684, filed Apr. 15, 1987, now abandoned, which in turn is acontinuation of Ser. No. 06/820,814, filed Jan. 17, 1986, now U.S. Pat.No. 4,677,127, which in turn is a continuation of Ser. No. 06/613,538,filed May 24, 1984, now abandoned, which in turn is a continuation ofSer. No. 06/439,545, filed Nov. 5, 1982, now abandoned.

BACKGROUND OF THE INVENTION

Blood sucking parasitic infestation on animals, especially theinfestation of pets by fleas, has been a continued problem in the art.On account of the complexity of the life cycle of the flea, none of themethods known to the prior art of controlling such parasites is entirelysatisfactory, especially since these methods are directed primarily tothe control of adult fleas in the coat of the host animal and do nottake into account the different juvenile stages of the fleas existing inthe animals coats as well as on the floor, on carpets, in bedding, onchairs, in the garden and in other places with which the infested animalusually comes into contact. Adult cat and dog fleas (Ctenocephalidesfelis and C. canis) live naturally in the coat of the cat or dog host.They feed on host blood and the females lay eggs in the coat. Since theeggs are not sticky, they quickly fall off and can be found on thefloor, carpets, animals' beddings, chairs used by the pets, the garden,the backyard, etc.

Thus, the total environment of the animal is infested with flea eggs,which in about two days hatch into larvae. There are three larvalstages, each lasting about three days. In the last stage the larvae spincocoons and transform to pupae. Under optimum conditions, i.e., 33° C.and 65% relative humidity, the eggs transform to pupae in about 8 to 10days. After a further period of approximately 8 days, the pupae developto young adult fleas in the cocoon still lying on the floor, thecarpets, the beddings, the chairs, etc. The young adult fleas wait untilthey sense the presence of an acceptable host animal and then emerge andattempt to jump onto it. Thus, it takes at least three weeks for eggs todevelop to young adults able to reinfest the host. However, the youngadults can remain for months, possibly as long as one year, in thecocoon, and in addition, under suboptimum conditions, it can take 4 to 5months for the eggs to develop into young adults. Fleas must have ablood meal in order to become sexually mature and therefore be able toreproduce. The blood must come from the correct type of host.

This long life cycle, occurring at sites other than on the animal, hasimportant implications for flea treatment applied to host animals. Evenif fleas in the coat of the animal can be controlled successfully, i.e.,if all adult fleas are killed by an active ingredient, the cat or dog isnevertheless exposed for weeks or even months to the risk ofreinfestation by the newly emerged adults present in the animal'senvironment.

Infestation of dogs and cats with fleas has several undesirable effectsfor the treated animals or the owner. Such undesirable effects maymanifest themselves in the form of local irritation or annoying itching,often leading to scratching. Quite a high number of animals becomeallergic to flea saliva, resulting in very itchy and crusty lumps on theanimal's body at the site of the bites. Normally these lumps reach adiameter of 3 mm or more and cause the animal to bite and scratch,leading to subsequent hair loss. The infested animals create a nervousreaction and become more and more unattractive and irritable.

Furthermore, animals which are infested by fleas are permanently exposedto the danger of being infected by Dipylidium, a tape worm which istransmitted by the fleas.

Flea infestation not only is extremely annoying for the infested animal,but also unpleasant for the owner who observes the unusual behavior of apet which is ill, suffering, and in need of help. In the prolongedabsence of a suitable host animal, newly hatched fleas on the floor arecompelled to attack humans (although they are not capable ofreproduction if human blood is their sole source of nutrition). Even inthe presence of the dog or cat, the owner may be bitten by the fleas.Moreover, some humans may suffer from allergic skin diseases as a resultof dog and cat fleas or their excrete.

A number of methods for the control of fleas are known, but these havevarious drawbacks. When using flea combs for example, the animal ownerhas no choice other than combing the animal intensively and frequently.Depending on the size of the animal, this may take from several minutesto an hour. Not every animal will always patiently put up with beingcombed, nor is every owner prepared to sacrifice his time for thisoperation.

The use of anti-flea shampoos in many cases is impossible since mostcats and a large number of dogs simply refuse to be given a bath or theycan only be given a bath when the owner resorts to using force, in whichcase water and shampoo will be splashed about. Furthermore, the effectof such bathing does not last for more than about a week and thelaborious procedure then must be repeated. Similar problems areencountered when using dips or rinses. Even the use of dusting powdersas a rule is not tolerated by the animal without resistance since ittakes several minutes to treat the entire surface of the coat uniformlyand some dust is bound to get into the mouth, nose, and eyes of theanimal. Even in the case of careful application, it is impossible toprevent the powder from being inhaled by the animal or its owner. Thereis virtually no way for the owner to avoid a more or less intensivecontact with the active ingredient.

When using sprays, an owner may experience an unpleasant surprise sincemost animals, particularly cats, take flight or react aggressively tothe noise of the spray. Moreover, sprays have all the drawbacksmentioned above for powders and, in addition, they disperse even morefinely in the atmosphere, which means that animals and their ownerssimply can not avoid inhaling them.

Fleas are frequently also controlled with flea collars which are veryeffective temporarily. A particular weakness of this method oftreatment, however, is that it is normally effective in a very limitedregion of the animal's body. In general, 100% kill is achieved in theregion of the neck and thorax; however, more remote parts of the bodyare hardly affected. Besides, many of these collars look unattractiveand may also irritate the animal. Today medallions are available whichcan be attached to the collar and which are said to be active. Thesemedallions are appealing to the eye, but their effectiveness isunsatisfactory since they do not come into sufficient contact with theanimal's coat. Several anti-flea organophosphorus compounds areavailable in the form of spot-on formulations. These are applied to alimited spot on the coat. In general, they exhibit good short-termactivity against adult fleas but when applied often, the compositionshave problematic toxicity. Some organophosphorus compounds areadministered orally but have narrow safety limits and must never beapplied simultaneously with other organophosphorus compounds.

On the whole it can be said that it has always been the objective ofprevious methods to kill the adult flea. Some of these methods can beapplied quite successfully to control adult fleas for a short period. Afact which has so far not been acknowledged is that, owing to theparticular life cycle of fleas, dogs and cats will be repeatedlyreinfested because, on the one hand, the animal can not avoid cominginto contact with the flea eggs, flea larvae and juvenile and adultfleas on the floor or in its immediate vicinity and, on the other hand,many pets again and again come into contact with infested members of thesame species. Constantly recurring reinfestation is not prevented byusing conventional pesticides.

DETAILED DESCRIPTION OF THE INVENTION

Surprisingly, it has been found that by specific modes of applicationand by using benzoylureas which block the development of juvenile fleastages, the vicious circle of constantly recurring reinfestation,described above in detail, can be brought to an end in simple manner,thereby preventing the fleas from reproducing and, in addition, keepingthe habitat of dogs and cats permanently free from fleas.

It has been found that by administering to dogs or cats orally orparenterally or by implant a larvicidally or ovicidally effective amountof a flea growth inhibiting benzoylurea, the reinfestation of dogs andcats by fleas can be drastically reduced or completely prevented.

It is known that some benzoylurea inhibit or completely suppress thefurther development of juvenile stages; however, this activity hasalways been observed when the active ingredient is applied direct to theparasites. In connection with the present invention, it is surprising,however, that the full activity is still achieved even when the activeingredient is administered to the host animal in relatively lowconcentrations and it reaches, in an indirect way, the adult flea viathe blood ingested and, additionally, the flea larvae (the actualtarget) when they feed upon the feces excreted by the adult fleas. Bykilling merely the adult fleas, which has so far been the objective ofmethods of control, the host animal is freed from fleas for a short timeonly. It has been found that fleas can only be effectively controlled ifthe development of new flea populations from the flea eggs issuccessfully prevented.

Target pests may be exposed to the benzoylureas in two ways. Thebenzoylurea is ingested in the blood meal by adult insects and pass fromadults to the egg where they are effective. Death may occur at the egg,larval, or pupal stage. Research on fleas indicates reduced eggproduction, high larval mortality and inability of adults to enclosefrom the pupal case. In addition to transmission to the egg, larvalfleas are exposed when they feed upon feces excreted by adult fleas.Flea feces contain large amounts of undigested blood taken from the hostand serve as a protein source for the developing flea.

Accordingly, the present invention embraces two aspects; namely theabove-described method of preventing dogs and cats from being reinfestedby fleas, and, at the same time, the suppression of the propagation offleas, or to put it more precisely, a method of preventing thepropagation of fleas, comprising the step of providing the fleas withnutrient blood which contains an effective amount of at least one of thebenzoylureas. This method also includes the aspect that the nutrientblood is provided to the fleas by feeding an effective amount of one ofthe benzoylurea to a host dog or a host cat and allowing the fleas tofeed on this circulating blood.

Flea growth inhibiting benzoylurea derivatives, which are also known as"dimiloids", are described in, for example, DE-OS-2,123,236;DE-OS-2,601,780; DE-OS-3,240,975; EP-72,438 and EP-42,533.

Compounds of this class and suitable for use in the method of thepresent invention are the following compounds of formula I ##STR1##wherein

R₁ is unsubstituted or substituted phenyl, naphthyl, pyridyl,pyridazinyl, pyrimidinyl or pyrazinyl,

R₂ is hydrogen or C₁ -C₆ alkyl,

R₃ is ##STR2##

R₄ to R₈ are each independently hydrogen, halogen, C₁ -C₆ -alkyl, C₁ -C₆haloalkyl, C₁ -C₆ alkoxy, C₁ -C₆ haloalkoxy or C₁ -C₆ alkylthio, and

X⁻ is an inorganic or organic cation, suitable inorganic cations beingalkali metal and alkaline earth metal cations and organic cations beingcharacterized by the group ##STR3## in which formulae, R₉ to R₁₂ areeach independently hydrogen, C₁ -C₂₀ alkyl, benzyl, or phenyl and R₁₃ ishydrogen or C₁ -C₂₀ alkyl e.g. H₄ N⁺, (CH₃)₄ N⁺, (C₂ H₅)₄ N⁺, (n-C₃ H₇)₄N⁺, (i-C₃ H₇)₄ N⁺, (n-C₄ H₉)₄ N⁺, ##STR4## n being a value from 8 to 15.

Particularly preferred are benzoylurea of the formula: ##STR5## wherein:

R^(a) is hydrogen; chloro; bromo; fluoro; methyl; trifluoromethyl;trifluoromethoxy; 2-chloro-1,1,2-trifluoroethoxy;2-bromo-1,1,2-triflouroethoxy; 1,1,2,2-tetrafluoroethoxy; or1,1,2,3,3,3-hexafluoroprop-1-oxy;

R^(b) is hydrogen or chloro; and

R^(c) is hydrogen; chloro; 5-trifluoromethylpyrid-2-yloxy; or3-chloro-5-trifluoromethylpyrid-2-yloxy;

at least one of R^(a) and R^(c) being other than hydrogen.

Preferred subgroups are those in which one of R^(a) and R^(b) is anether group. Thus a first preferred subgroup are benzoylureas of FormulaII in which R^(a) is hydrogen, methyl, or chloro; R^(b) is hydrogen; andR^(c) is 5-trifluoromethylpyrid-2-yloxy or3-chloro-5-trifluoromethylpyrid-2-yloxy. A second preferred subgroup arebenzoylureas of Formula II in which R^(a) is2-chloro-1,1,2-trifluoromethoxy, 2-bromo-1,1,2-trifluoromethoxy;1,1,2,2-tetrafluoroethoxy; or 1,1,2,3,3,3-hexafluoroprop-1-oxy; R^(b) ischloro; and R^(c) is chloro, that is anN-(2,6-difluorobenzoyl)-N'-(3,6-dichloro-4-R^(a) -phenyl)urea orN-(2,6-difluorobenzoyl)-N'-(3,5-dichloro-4-R^(a) -phenyl)urea.

Representative examples of particularly preferred individual compoundsare: ##STR6##

It is an essential feature of the present invention that the activebenzoylurea is administered in such a manner that it can be ingested bythe adult sucking flea with the circulating blood of the host animal andcan then exhibit activity against the juvenile flea stages. Inaccordance with the present invention, this is achieved with severalforms of application, e.g. by administering a formulated activeingredient orally. In this case, the term "formulated" means in the formof a powder, a tablet, a granulate, a capsule, an emulsion, a foam, etc.The preparation does not necessarily have to be administered to theanimal direct; it may be convenient to mix it with the animal's feed.

Oral application can be in the form of tablets, capsules, lick-stones,bolus, drinking water, or granules. Parenteral administration can beaccomplished by means of injection, implantation, or transdermalapplication.

In addition to containing adjuvants conventionally employed in the artof formulation, the compositions to be administered orally may of coursecontain further additives which stimulate voluntary ingestion by theanimal, e.g. suitable scents or flavorings.

Owing to its simplicity, oral application is one of the preferredobjects of the present invention. A further mode of application isparenteral application, e.g. by subcutaneous, intravenous orintramuscular injection or by means of a sustained action preparation inthe form of an implant or other depot formulation.

Methods of oral application include but are not limited to compoundspremixed in dog and cat food, fed in biscuits or treats, chewabletablets, water-dissolvable capsules or tablets, water-soluble compoundsapplied with a dropper into water or materials applied in any form ontodog food. Implant include any device applied into the animal for releaseof compounds to control fleas.

Percutaneous administration is conveniently accomplished bysubcutaneous, dermal, intramuscular and even intravenous application ofthe injectable formulation. Conventional needle-type injection devicesas well as needle-less air-blast injection devices can be used.

It is possible to delay or sustain the permeation of the activeingredient through the animal's living tissues by proper formulation.For example, a very insoluble compound may be used. In this case, theslight solubility of the compound causes sustained action because thebody fluids of the animal can dissolve only a small amount of thecompound at any one time. Sustained action of the active ingredient canalso be obtained by formulating the compound in a matrix which willphysically inhibit dissolution. The formulated matrix is injected intothe body where it remains as a depot from which the compound slowlydissolves.

Matrix formulations, now known in the art, are formulated in waxysemisolids such as vegetable waxes and high molecular weightpolyethylene glycols.

Very effective sustained action is obtained by introducing into theanimal or implant containing one of the active ingredients. Suchimplants are now well known in veterinary art and are usually made of asilicone-containing rubber. The active ingredient is dispersed through asolid rubber implant or is contained inside a hollow implant. Care mustbe taken to choose an active ingredient which is soluble in the rubberform which the implant is made, since it is dispersed by firstdissolving in the rubber and then leaching out of the rubber into thebody fluids of the treated animal.

The rate at which active ingredient is released from an implant, andhence the length of time during which the implant remains effective, iscontrolled with good accuracy by the proper adjustment of theconcentration of the compound in the implant, the external area of theimplant, and the formulation of the polymer from which the implant ismade.

Administration of the active ingredient by means of an implant is afurther particularly preferred embodiment. Such administration is highlyeconomical and efficacious because a properly designed implant maintainsa constant concentration of the compound in the tissues of the hostanimal. An implant can be designed to supply compound for several monthsand is easily inserted in the animal. No further handling of the animalor concern over the dosage is necessary after the insertion of theimplant.

The formulation of veterinary additives in animal feed is an extremelywell-known art. It is usual to formulate the compound first as a premixin which the active ingredient is dispersed in a liquid or particulatesolid carrier. The premix may conveniently contain from about 1 to 800 gof compound per kilogram, depending on the desired concentration in thefeed. As is known in the art, many active -ingredients can be hydrolyzedor degraded by constituents of animal feed. Such compounds are routinelyformulated in protective matrices such as gelatin before addition to thepremix.

Therefore, the present invention is also directed to a method ofsystemically preventing the reinfestation of dogs and cats by fleas,which method comprises administering to said host animals orally,parenterally or by implant a larvicidally or ovicidally effective amountof a flea growth inhibiting benzoylurea derivative.

The present invention also relates to a method of preventing thepropagation of fleas, comprising the step of providing the fleas withnutrient circulating blood which contains an effective amount of a fleagrowth inhibiting benzoylurea or more specifically the present inventionalso relates to the method of preventing the propagation of fleas byfeeding an effective amount of a flea growth inhibiting substance, ascharacterized above, to the host animal and letting the fleas feedthereon.

The benzoylurea is conveniently applied in a dose of 0.01 to 800,preferably 0.5 to 200, most preferably 1 to 30, mg/kg body eight, basedon the host animal, with oral administration being preferred. A gooddose for regular administration is in general in the range from 1 to 100mg/kg body weight of the host animal. Doses are usefully regularlyrepeated at daily to weekly intervals.

The total dose of the benzoylurea can vary from one genus of animal tothe other and can even vary within the same genus since said dosedepends, inter alia, on the weight and constitution of the animal.

In the method of the present invention, the benzoylurea normally is notapplied in pure form, but preferably in the form of a composition which,in addition to containing the active ingredient, contains applicationpromoters which are tolerated by the host animal. Naturally, in additionto the method of controlling juvenile development stages in accordancewith the present invention, the adult fleas may also be controlled byconventional methods. However, these additional measures are notabsolutely necessary.

The composition to be applied in the method of this invention usuallycontains 0.1 to 99% by weight, preferably 0.1 to 95% by weight, of thebenzoylurea, and 99.9 to 1% by weight, preferably 0.1 to 25% by weight,of a solid or liquid non-toxic adjuvant, including 0 to 25% by weight,preferably 0.1 to 25% by weight, of a nontoxic surfactant.

Whereas commercial products are preferably formulated as concentrates,the end user will normally employ dilute formulations.

The compositions may also contain further ingredients, such asstabilizers, antifoams, viscosity regulators, binders, tackifiers aswell as other active ingredients for obtaining special effects.

Materials known from veterinary practice as being suitable for beingadministered orally, parenterally or by implant may be employed asformulation assistants. A number of examples are cited below.

Suitable carriers are especially fillers, such as sugars, for examplelactose, saccharose, mannitol or sorbitol, cellulose preparations and/orcalcium phosphates, for example tricalcium phosphate or calcium hydrogenphosphate, also binders, such as starch pastes using, for example, corn,wheat, rice or potato starch, gelatine, tragacanth, methylcelluloseand/or, if desired, disintegrators, such as the above-mentionedstarches, also carboxymethyl starch, crosslinked polyvinylpyrrolidone,agar, alginic acid or a salt thereof, such as sodium alginate. Adjunctsare especially flow-regulating agents and lubricants, for examplesilica, talc, stearic acid or salts thereof, such as magnesium stearateor calcium stearate, and/or polyethylene glycol. Dragee cores can beprovided with suitable coatings that may be resistant to gastric juices,e.g. concentrated sugar solutions which may contain gum arabic, talc,polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, orlacquer in suitable organic solvents or solvent mixtures or, for theproduction of coatings that are resistant to gastric juices, solutionsof suitable cellulose preparations, such as acetylcellulose phthalate orhydroxypropylmethylcellulose phthalate. Colorings, flavorings orpigments can be added to the tablets or dragee coatings, for example,for identification purposes or to indicate different dose of activeingredients.

Further orally administrable preparations are dry-filled capsulesconsisting of gelatine and also soft, sealed capsules consisting ofgelatine and a plasticizer, such as glycerol or sorbitol. The dry-filledcapsules may contain the active ingredient in the form of a granulate,for example in admixture with fillers, such as lactose, binders, such asstarches, and/or glidants, such as talc or magnesium stearate, andoptionally stabilizers. In soft capsules, the active ingredient ispreferably dissolved or suspended in suitable liquids, such as fattyoils, paraffin oil or liquid polyethylene glycols, it being possiblealso to add stabilizers. Preferred are, inter alia, capsules that can beeasily bitten through or swallowed without being chewed.

Especially suitable for parenteral administration are aqueous solutionsof an active ingredient in water-soluble form, for example awater-soluble salt, also suspensions of the active ingredient, sch ascorresponding oily injection suspensions, e.g. suitable lipophilicsolvents or vehicles, such as fatty oils, for example sesame oil, orsynthetic fatty acid esters, for example ethyl oleate, or triglycerides,or aqueous injection suspensions that contain viscosity-increasingsubstances, for example sodium carboxymethylcellulose, sorbitol and/ordextran, and, optionally, also stabilizers.

The preparations of the present invention can be manufactured in amanner known per se, for example by means of conventional mixing,granulating, confectioning, dissolving or lyophilizing processes. Forexample, pharmaceutical preparations for oral administration can beobtained by combining the active ingredient with solid carriers,optionally granulating a resultant mixture, and processing the mixtureor granulate, if desired or necessary after the addition of suitableadjuncts, to form tablets or dragee cores.

The following Examples illustrate the invention described hereinbefore,but do not limit its scope in any way. In these examples, the activeingredient can include any ofN-(2,6-difluorobenzoyl)-N'-[3-(3-chloro-5-trifluoromethylpyrid-2-yloxy)-4-bromophenyl]urea,N-(2,6-difluorobenzoyl)-N'-[3-(3-chloro-5-trifluoromethylpyrid-2-yloxy)-4-methylphenyl]urea,N-(2,6-difluorobenzoyl)-N'-[3-(3-chloro-5-trifluoromethyl-pyrid-2-yloxy)-4-chlorophenyl]urea,N-(2,6-difluorobenzoyl)-N'-[3-(3-chloro-5-trifluoromethylpyrid-2-yloxy)-4-fluorophenyl]-urea,N-(2,6-difluorobenzoyl)-N'-[3-(5-trifluoromethylpyrid-2-yloxy)-4-bromophenyl]urea,N-(2,6-difluorobenzoyl)-N'-[3-(5-trifluoromethylpyrid-2-yloxy)-4-methylphenyl]urea,N-(2,6-difluorobenzoyl)-N'-[3-(5-trifluoromethylpyrid-2-yloxy)-4-chlorophenyl]urea,N-(2,6-difluorobenzoyl)-N'-[3-(5-trifluoromethylpyrid-2-yloxy)-4-fluorophenyl]urea,N-(2,6-difluorobenzoyl)-N'-[3,5-dichloro-4-(2-chloro-1,1,2-trifluoroethoxy)phenyl]urea,N-(2,6-difluorobenzoyl)-N'-[3,6-dichloro-4-(2-chloro-1,1,2-trifluoroethoxy)phenyl]urea,N-(2,6-difluorobenzoyl)-N'-[3,5-dichloro-4-(1,1,2,3,3,3-hexafluoroprop-2-oxy)phenyl]-urea,N-(2,6-difluorobenzoyl)-N'-[3,6-dichloro-4-(1,1,2,3,3,3-hexafluoroprop-1-oxy)phenyl]-urea,N-(2,6-difluorobenzoyl)-N'-[3,5-dichloro-4-(2-bromo-1,1,2-trifluoroethoxy)phenyl]urea,N-(2,6-difluorobenzoyl)-N'-[3,6-dichloro-4-(2-bromo-1,1,2-trifluoroethoxy)phenyl]urea,N-(2,6-difluorobenzoyl)-N'-[3,5-dichloro-4-(1,1,2,2-tetrafluoroethoxy)phenyl]urea,andN-(2,6-difluorobenzoyl)-N'-[3,6-dichloro-4-(1,1,2,2-tetrafluoroethoxy)phenyl]urea.

EXAMPLE 1

Tables containing 25 mg of active ingredient can be manufactured asfollows:

    ______________________________________                                        Constituents (for 1000 tablets)                                               ______________________________________                                        active ingredient     25.0 g                                                  lactose               100.7 g                                                 wheat starch          7.5 g                                                   polyethylene glycol (mol. wt. 6000)                                                                 5.0 g                                                   talc                  5.0 g                                                   magnesium stearate    1.8 g                                                   demineralized water   q.s                                                     ______________________________________                                    

Manufacture

All the solid ingredients are first forced through a sieve having a meshwidth of 0.6 mm. Then the active ingredient, the lactose, the talc, themagnesium stearate and half of the starch are mixed. The other half ofthe starch is suspended in 40 ml of water and this suspension is addedto a boiling solution of the polyethylene glycol in 100 ml of water. Theresulting starch paste is added to the main batch and the mixture, ifnecessary with the addition of water, is granulated. The granulate isdried overnight at 35° C., forced through a sieve having a mesh width of1.2 mm and pressed to form tablets having a diameter of approximately 6mm that are concave on both sides.

EXAMPLE 2

Tablets containing 0.02 g of active ingredient are manufactured asfollows:

    ______________________________________                                        Composition                                                                   ______________________________________                                        active ingredient                                                                              200.00 g                                                     lactose          290.80 g                                                     potato starch    24.70 g                                                      stearic acid     10.00 g                                                      talc             200.00 g                                                     magnesium stearate                                                                             2.50 g                                                       colloidal silica 32.00 g                                                      ethanol          q.s.                                                         ______________________________________                                    

A mixture of the active ingredient, the lactose and 194.70 g of thepotato starch is moistened with an ethanolic solution of the stearicacid and granulated through a sieve. After drying, the remainder of thepotato starch, the talc, the magnesium, and the colloidal silica areadmixed and the mixture is pressed to form 0.1 g tablets which, ifdesired, can be provided with breaking grooves for finer adjustment ofthe dosage.

EXAMPLE 3

Capsules containing 0.025 g of the active ingredient can be manufacturedas follows:

    ______________________________________                                        Composition (for 1000 capsules)                                               ______________________________________                                        active ingredient    25.00 g                                                  lactose              249.00 g                                                 gelatine             2.00 g                                                   corn starch          10.00 g                                                  talc                 15.00 g                                                  water                q.s.                                                     ______________________________________                                    

The active ingredient is mixed with the lactose and the mixture ismoistened uniformly with an aqueous solution of the gelatine andgranulated through a sieve having a mesh width of 1.2-1.5 mm. Thegranulate is mixed with dried corn starch and the talc is introduced inportions of 300 mg into hard gelatine capsules (size 1).

EXAMPLE 4 Premix (Feed Additive)

0.25 parts by weight of active ingredient and

4.75 parts of secondary calcium phosphate, or China clay, aerosol orcarbonate or line are homogeneously mixed with

95 parts of an animal feed.

EXAMPLE 5 Injection Solution

8 parts by weight active ingredient

3.6 parts of acetic acid

88.4 parts of water for injection

The acetic acid and the water are added to the active ingredient and themixture is stirred until everything has dissolved. The solution is thenfiltered and sterilized by a suitable method. pH of the solution: 5.0.

EXAMPLE 6 Emulsifiable Concentrate

20 parts of active ingredient are mixed with

20 parts of emulsifier, e.g. a mixture of alkylarylpolyglycol ether withalkylaryl sulphonates, and

60 parts of solvent until the solution is completely homogeneous.

By diluting this concentrate with water it is possible to obtain anemulsion of the desired concentration.

EXAMPLE 7 Solutions (For Dilution With Drinking Water)

15% active ingredient in 2,2-dimethyl-4-hydroxy methyl1-1,3-dioxolane

10% active ingredient in diethylene glycol monethyl ether

10% active ingredient in polyethylene glycol (mol. wt. 300)

5% active ingredient in glycerol

EXAMPLE 8 Soluble Powder

25 parts of active ingredient

1 part of sodium lauryl sulfate

3 parts of colloidal silica

71 parts of urea

The constituents are mixed and the mixture is finely ground in asuitable mill.

Other biocidal active ingredients or agents which are inert towards theactive ingredients and acceptable to the animals to be treated, ormineral salts or vitamins can be admixed to the compositions described.

In a manner analogous to that described in the formulation Examples 1 to8, it is possible to manufacture corresponding preparations containing acompound of the classes (a), (b) or (c) as defined above.

What is claimed is:
 1. A method of suppressing flea reinfestation in thecoat of a host cat or dog which comprises providing to the circulatingblood of the host through oral or parenteral administration or throughimplantation, an amount of a benzoylurea which, when ingested by anadult flea infesting said host and feeding on said blood, is nonlethalto the ingesting adult flea but which inhibits, at a site other than onthe host, the development of juvenile stages of progeny of the ingestingadult flea, said benzoylurea having the formula: ##STR7## wherein: R^(a)is hydrogen; chloro; bromo; fluoro; methyl; trifluoromethyl;trifluoromethoxy; 2-chloro-1,1,2-trifluoroethoxy;2-bromo-1,1,2-triflouroethoxy; 1,1,2,2-tetrafluoroethoxy; or1,1,2,3,3,3-hexafluoroprop-1-oxy;R^(b) is hydrogen or chloro; and R^(c)is hydrogen; chloro; 5-trifluoromethylpyrid-2-yloxy; or3-chloro-5-trifluoromethylpyrid-2-yloxy;at least one of R^(a) and R^(c)being other than hydrogen.
 2. The method according to claim 1 in whichin said benzoylurea R^(a) is 2-chloro-1,1,2-trifluoroethoxy,2-bromo-1,1,2-trifluoroethoxy; 1,1,2,2-tetrafluoroethoxy; or1,1,2,3,3,3-hexafluoroprop-1-oxy; R^(b) is chloro; and R^(c) is chloro.3. The method according to claim 2 wherein said benzoylurea isN-(2,6-difluorobenzoyl)-N'-(3,6-dichloro-4-R^(a) -phenyl)urea in whichR^(a) is 2-chloro1,1,2-trifluoroethoxy, 2-bromo-1,1,2-trifluoroethoxy;1,1,2,2-tetrafluoroethoxy; or 1,1,2,3,3,3-hexafluoroprop-1-oxy.
 4. Themethod according to claim 3 wherein said benzoylurea isN-(2,6-difluorobenzoyl)-N'-(3,5-dichloro-4-R^(a) -phenyl)urea in whichR^(a) is 2-chloro-1,1,2-trifluoroethoxy, 2-bromo-1,1,2-trifluoroethoxy;1,1,2,2-tetrafluoroethoxy; or 1,1,2,3,3,3-hexafluoroprop-1-oxy.
 5. Themethod according to claim 1 wherein said benzoylurea is administeredorally.
 6. The method according to claim 5 wherein the amount of saidbenzoylurea administered is from 0.01 to about 800 mg per kg of bodyweight.
 7. The method according to claim 6 wherein the amount of saidbenzoylurea administered is from 1 to about 30 mg per kg of body weight.8. The method according to claim 6 wherein the amount of saidbenzoylurea administered is from 0.5 to about 200 mg per kg of bodyweight.
 9. The method according to claim 5 in which said benzoylurea isN-(2,6-difluorobenzoyl)-N'-[3,5-dichloro-4-(2-chloro-1,1,2-trifluoro-1-ethoxy)phenyl]urea.10. The method according to claim 5 in which said benzoylurea isN-(2,6-difluorobenzoyl)-N'-[3,6-dichloro-4-(2-chloro-1,1,2-trifluoro-1-ethoxy)phenyl]urea.11. The method according to claim 5 in which said benzoylurea isN-(2,6-difluorobenzoyl)-N'-[3,5-dichloro-4-(1,1,2,3,3,3-hexafluoroprop-1-oxy)phenyl]-urea.12. The method according to claim 5 in which said benzoylurea isN-(2,6-difluorobenzoyl)-N'-[3,6-dichloro-4-(1,1,2,3,3,3-hexafluoroprop-1-oxy)phenyl]-urea.13. The method according to claim 5 in which said benzoylurea isN-(2,6-difluorobenzoyl)-N'-[3,5-dichloro-4-(2-bromo-1,1,2-trifluoro-1-ethoxy)phenyl]urea.14. The method according to claim 5 in which said benzoylurea isN-(2,6-difluorobenzoyl)-N'-[3,6-dichloro-4-(2-bromo-1,1,2-trifluoroethoxy)phenyl]urea.15. The method according to claim 5 in which said benzoylurea isN-(2,6-difluorobenzoyl)-N'-[3,5-dichloro-4-(1,1,2,2-tetrafluoroethoxy)phenyl]urea.16. The method according to claim 5 in which said benzoylurea isN-(2,6-difluorobenzoyl)-N'-[3,6-dichloro-4-(1,1,2,2-tetrafluoroethoxy)phenyl]urea.17. A method of suppressing flea reinfestation in the coat of a host cator dog which comprises providing to the circulating blood of the host,through oral or parenteral administration or through implantation, anamount of a benzoylurea which, when ingested by an adult flea infestingsaid host and feeding on said blood, is nonlethal to the ingesting adultflea but which inhibits, at a site other than on the host, thedevelopment of juvenile stages of progeny of the ingesting adult flea,said benzoylurea having the formula: ##STR8## wherein: R^(a) ishydrogen, methyl, or chloro andR^(c) is 5-trifluoromethylpyrid-2-yloxyor 3-chloro-5-trifluoromethylpyrid-2-yloxy.
 18. The method according toclaim 17 wherein said benzoylurea is administered orally.
 19. The methodaccording to claim 18 in which said benzoylurea isN-(2,6-difluorobenzoyl)-N'-[3-(3-chloro-5-trifluoromethylpyrid-2-yloxy)-4-bromophenyl]urea.20. The method according to claim 18 in which said benzoylurea isN-(2,6-difluorobenzoyl)-N'-[3-(3-chloro-5-trifluoromethylpyrid-2-yloxy)-4-methylphenyl]urea.21. The method according to claim 18 in which said benzoylurea isN-(2,6-difluorobenzoyl)-N'-[3-(3-chloro-5-trifluoromethylpyrid-2-yloxy)-4-chlorophenyl]urea.22. The method according to claim 18 in which said benzoylurea isN-(2,6-difluorobenzoyl)-N'-[3-(3-chloro-5-trifluoromethylpyrid-2-yloxy)-4-fluorophenyl]-urea.23. The method according to claim 18 in which said benzoylurea isN-(2,6-difluorobenzoyl)-N'-[3-(5-trifluoromethylpyrid-2-yloxy)-4-bromophenyl]urea.24. The method according to claim 18 in which said benzoylurea isN-(2,6-difluorobenzoyl)-N'-[3-(5-trifluoromethylpyrid-2-yloxy)-4-methylphenyl]urea.25. The method according to claim 18 in which said benzoylurea isN-(2,6-difluorobenzoyl)-N'-[3-(5-trifluoromethylpyrid-2-yloxy)-4-chlorophenyl]urea.26. The method according to claim 18 in which said benzoylurea isN-(2,6-difluorobenzoyl)-N'-[3-(5-trifluoromethylpyrid-2-yloxy)-4-fluorophenyl]urea.